SELECTIVE BLOCKAGE OF DELTA-OPIOID RECEPTORS PREVENTS THE DEVELOPMENT OF MORPHINE-TOLERANCE AND DEPENDENCE IN MICE

Recently, we demonstrated that delta opioid binding sites are involved in the development of morphine tolerance and dependence. In our present work, we studied the effect of the potent and selective delta antagonist, naltrindole (NTI), and its nonequilibrium analog, naltrindole 5'-isothiocyanate (5'-NTII), on the development of morphine tolerance and dependence in mice. In the acute model, mice injected with 100 mg/kg of morphine sulfate s.c. displayed acute tolerance 4 hr later as evidenced by a > 3-fold increase of the ED50 of morphine sulfate when compared to that of control mice. The acute tolerance was accompanied by the development of acute physical dependence as seen by the dramatic decrease in the amount of naloxone required to precipitate withdrawal jumping. Likewise, in the chronic model s.c. implantation of morphine pellets (75 mg free base) for 3 days produced tolerance and physical dependence. The ED50 of morphine sulfate in this case was increased by about 19-fold and the amount of naloxone needed to precipitate withdrawal jumping was 40 times lower than that required for acutely dependent mice. The development of acute tolerance and dependence was suppressed markedly in mice pretreated with NTI before induction of tolerance and dependence with 100 mg/kg of morphine sulfate. Multiple administration of either NTI or 5'-NTII before and during implantation with morphine base pellets also inhibited substantially the development of morphine tolerance and dependence. The effects of NTI and 5'-NTII on these two adaptive phenomena were thought to occur solely by blockage of delta opioid receptors because the activity of the selective mu opioid receptor agonist, [D-Ala2,MePhe4,Gly-ol5]enkephalin was unaffected by the two antagonists. It was concluded that delta, as well as mu, opioid receptors play key roles in the development of opiate tolerance and physical dependence. Also, the use of these delta opioid receptor antagonists allows a way to prevent opiate tolerance and physical dependence without compromising the antinociceptive activity of mu opioid receptor agonists such as morphine.